This project investigates basic and clinical aspects of ovarian function in order to improve care for women with ovarian disorders. Ovarian dysfunction not only results in loss of fertility but also the loss of ovarian hormones that sustain life and health. Our research addresses both these problems. Our study on premature ovarian failure, which affects 1% of women under 40 years of age, has revealed that many affected women have evidence of antral follicle development, as determined by ultrasound imaging. Furthermore, biopsy of these follicles has shown that 60% demonstrate premature luteinization, indicating a potentially reversible functional disorder. A clinical trial employing specific treatment for these patients is under development. A placebo-controlled treatment trial utilizing alternate day prednisone for women who demonstrate biopsy proven immune attack upon the ovary is in progress. Additional studies have shown that two-thirds of our patients with premature ovarian failure demonstrate significantly reduced bone mineral density placing them at a 3-fold risk of fracture, despite being on conventional hormone replacement treatments. A clinical study of alternate hormone replacement regimens aiming to improve bone protection for these women is under development. This year we have extended our work to the polycystic ovary syndrome (PCOS) or chronic hyperandrogenic anovulation. This disorder affects 10-30% of women in the U.S., with the higher incidence seen in minority populations. During early life these women suffer from reduced fertility and hirsutism, and in later years they bear increased risk for diabetes mellitus, coronary disease and reproductive tract neoplasia. While its etiology is unclear, a central feature of the syndrome is disordered ovarian folliculogenesis. Based on the hypothesis that excess androgens may interfere with normal follicular development through an androgen receptor mediated mechanism, a trial of anti-androgen pharmacological blockade to try to improve fertility in women with PCOS has been initiated.